High blood pressure occurs when smaller arteries become abnormally narrow, which causes the blood to exert excessive pressure against the vessel walls. As a consequence, the heart must work harder to maintain the blood flow against this increased resistance. Over an extended period of time, this may lead to enlargement and damage of the heart (cardiac hypertrophy). Although the body can tolerate an increase in blood pressure for months or even years, eventually, damage to blood vessels of the kidneys, the brain, and/or the eyes can occur. Hypertension may also lead to congestive heart failure.
In most hypertensives, both the systolic and diastolic pressures are raised. However, in some older people, “isolated” systolic hypertension may occur. A rise in diastolic pressure used to be considered more serious than a rise in systolic pressure, but now it is accepted that this isolated form of systolic hypertension puts affected people at considerable risk of brain damage due to stroke.
It is estimated that approximately 50 million people in the US have high blood pressure. About half of these people never know it because of the lack of specific symptoms. High blood pressure is therefore sometimes called the “silent killer.” It is further estimated that about 50 percent of all hypertensive people are women.
Of the roughly 50 million adult Americans with high blood pressure, only about 27% have their hypertension under control. Of those who have been diagnosed, about 27% are being treated with medications, but are failing to control the condition, and nearly 15% are not participating in any treatment at all.
In most cases of hypertension, the cause is unknown. This is called primary hypertension. In about 5 to 10 percent of people, high blood pressure is a secondary symptom of some other medical condition. For example, there might be an organic cause such as kidney disease, tumor of the adrenal glands, heart defects, or disorders of the nervous system.
Aggressive drug treatment of long-term high blood pressure can significantly reduce the incidence of death from heart disease and other causes in both men and women. In people with diabetes, controlling both blood pressure and blood glucose levels prevents serious complications of that disease. If patients have mild hypertension and no heart problems, then lifestyle changes may suffice to control the condition, if carried out with determination. For more severe hypertension or for mild cases that do not respond to changes in diet and lifestyle within a year, drug treatment is usually necessary. A single-drug regimen can often control mild to moderate hypertension. More severe hypertension often requires a combination of two or more drugs. Prolonged-release drugs are being developed so that they are most effective during early morning periods, when patients are at highest risk for heart attack or stroke.
Hypertensive Medication Therapy
A number of oral and parenteral medications are available for the treatment of hypertension.
Beta-Blockers: Beta-blockers (beta-adrenergic blockers) work by reducing sympathetic nerve input to the heart. Thus, the heart beats less often per minute and with less force. Subsequently, the heart reduces its work, and blood pressure drops. Beta-blockers include propranolol, metoprolol, atenolol, and many others.
Diuretics: Diuretics cause the body to excrete water and salt. This leads to a reduction in plasma volume, which subsequently lowers systemic blood pressure. Diuretics include furosemide, hydrochlorothiazide, and spironolactone.
Angiotensin Converting Enzyme (ACE) Inhibitors: Angiotensin Converting Enzyme (ACE) inhibitors work by preventing the body's production of angiotensin II, a hormone that normally causes blood vessels to narrow. Consequently, the vessels remain wider, which lowers blood pressure. Angiotensin II also normally stimulates the release of another hormone, called aldosterone, which is responsible for the body's retention of sodium. Hence, in addition to creating wider vessels, ACE inhibitors mimic the effect of diuretics to a certain extent. As a result, blood vessels are subject to less pressure, and the heart performs less work. Examples of ACE inhibitors include enalapril, captopril, and lisinopril.
Angiotensin II Antagonists: Relatively new to the world of blood pressure treatment, angiotensin II antagonists are primarily used for patients who develop a cough as a side effect of taking ACE inhibitors. This medication antagonizes angiotensin II, thus inhibiting its effects. Examples include losartan and valsartan.
Calcium Channel Blockers: Calcium channel blockers keep calcium from entering the muscle cells of the heart and blood vessels. The heart and vessels relax, allowing blood pressure to go down. Some calcium channel blockers are nifedipine, verapamil, and diltiazem.
Alpha-Blockers: Alpha-blockers (alpha-adrenergic blockers) target the nervous system to relax blood vessels, allowing blood to pass more easily. Examples of alpha blockers are doxazosin, prazosin, and terazosin.
Alpha-Beta-Blockers: Alpha-beta-blockers (alpha- and beta-adrenergic blockers) basically have the same effect as a combined alpha-blocker and beta-blocker. They target the nervous system to relax the blood vessels, as well as work to slow the heartbeat. As a result, less blood is pumped through wider vessels, decreasing the overall blood pressure. Alpha-beta-blockers include labetalol and carvedilol.
Vasodilators: This category of medication works by relaxing the muscle in the blood vessel wall. Hydralazine and minoxidil are both generic forms of vasodilators.
Hypertensive Medication Efficacy: Research now indicates that beta-blockers, diuretics, and ACE inhibitors all reduce the risk for fatal and nonfatal cardiovascular events. As first-line treatment for most people with hypertension but no comorbid conditions, experts generally recommend beta-blockers or diuretics, which are inexpensive, safe, and effective. Some individuals, however, may have special requirements that call for specific drugs or combinations. Diuretics continue to be the best choice for older adults and for many African-Americans, who are more likely to be salt-sensitive and so respond well to these drugs. Isolated high systolic pressure is usually treated with a diuretic; adding a beta-blocker may improve outcome. For diabetics, the best drugs are beta-blockers or angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors have been shown to delay the onset and progression of kidney disease by 30% to 60% and to limit progression of other complications. Beta-blockers are less expensive and one study found that they were as effective as ACE inhibitors in reducing diabetic complications, although more studies are needed. Myocardial infarction (MI) survivors are usually given beta-blockers and sometimes ACE inhibitors to prevent a second MI. People with heart failure should be given ACE inhibitors and diuretics; specific drugs in these classes may be particularly beneficial for these patients because they reduce left ventricle hypertrophy.
It is very important to rigorously maintain a drug regimen. According to a recent study, patients who discontinue antihypertensive therapy, particularly smokers and younger adults, are at a significantly increased risk for stroke. On an encouraging note, one major study found that people taking blood pressure drugs did not experience any greater decline in the general quality of life or daily functioning over five years than did people who were not on blood pressure medication. In all cases, healthy lifestyle changes must accompany any drug treatment.
Hypertensive Medication Side Effects: All drugs used for hypertension have side effects. Common side effects include fatigue, coughing, skin rash, sexual dysfunction, depression, cardiac dysfunction, or electrolyte abnormalities. Some of these are distressing, and ongoing patient compliance may be difficult. Some clinicians have been concerned about the long-term effects of anti-hypertensive drugs on mental processes. A recent study found that brain scans of people who took calcium channel blockers or “loop” diuretics (e.g., furosemide, so called due to diuretic activity on a specific structure in the kidney known as the loop of Henle) detected changes in brain tissue; those who took beta-blockers had no such changes. This is an isolated study and more research is needed to confirm the findings. In spite of worrisome reports of serious side effects associated with some calcium channel blockers, and despite recommendations by a major expert group for wider use of beta-blockers and diuretics, prescriptions for calcium-channel blockers have increased and beta-blockers have decreased over recent years.
Carotid Sinus
The carotid sinus is a dilated area located at the bifurcations of the carotid arteries, and contains baroreceptors that control blood pressure by mediating changes in heart rate. The carotid body is a chemoreceptor located near the bifurcations of the carotid arteries, and monitors changes in oxygen content of the blood and helps control respiratory activity. In most people, the baroreceptors increase their firing rate in response to increased blood pressure, leading to a decrease in heart rate and systemic blood pressure. Both the carotid body and the carotid sinus are supplied with afferent fibers by the carotid sinus nerve, a branch of the glossopharyngeal nerve.
Arterial Baroreceptor Reflex
The maintenance of arterial blood pressure at adequate levels to perfuse the tissues during different conditions is a basic requirement for the survival of mammals, and is achieved by many complex neurohumoral (i.e., neurotransmitter) mechanisms. The main purpose of the baroreflex function is to provide rapid and efficient stabilization of arterial blood pressure on a beat-to-beat basis by means of strategically located arterial sensors which are sensitive to high blood pressure and are known as arterial baroreceptors. The receptor endings of this neural system terminate primarily in the adventitia (i.e., the outer layer) of the carotid sinus and aortic arch with their soma (i.e., cell bodies) located in the petrosal and nodose ganglia, respectively.
At each arterial systole, stretching of these sensors depolarizes them, which triggers action potentials that travel centrally to synapse onto neurons in the nucleus tractus solitarii (NTS, a.k.a. solitary tract nucleus) in the dorsal medulla. These second-order neurons project to the caudal ventrolateral medulla (CVLM) where they synapse with inhibitory neurons that in turn project to the rostral ventrolateral medulla (RVLM) and synapse with bulbospinal sympathoexcitatory neurons located in that area. In parallel, the second-order neurons maintain a tonic excitatory influence upon preganglionic parasympathetic neurons located in the dorsal nucleus of the vagus, rostral ventromedial medulla (RVMM), and mainly in the nucleus ambiguus. Thus, arterial baroreceptors maintain moment-to-moment control of both sympathetic and vagal innervation of the cardiovascular system. Modulation of this system is not restricted to medullary areas of neurons, but is also influenced by supramedullary areas.
Although arterial baroreceptors are capable of acute and chronic resetting to high levels of arterial pressure, baroreflex dysfunction has been reported in arterial hypertension and other cardiovascular diseases both in clinical and experimental hypertension. There are data in the literature showing that the impairment of baroreflex sensitivity can be either a consequence or a cause of arterial hypertension. Changes in vascular structure and distensibility can occur in the aortic arch and sinoaortic vessel walls, for example, with aging, arteriosclerosis, and diabetes, which decrease baroreceptor activity and consequently can contribute to the development of arterial hypertension. There is evidence that human hypertension may be induced or aggravated by impaired baroreceptor reflex control. On the other hand, there is strong evidence that baroreceptor reflex impairment could be a consequence, rather than a cause, of hypertension both in human and experimental animals.
Electrical Stimulation for the Treatment of Hypertension
Electrical stimulation of the carotid sinus was proposed over two decades ago as a therapy for hypertension and angina pectoris. In 1989, Peters, et al. investigated the effects of stimulation frequency and amplitude on hypertension. [See Peters, et al. “Temporal and spatial summation caused by aortic nerve stimulation in rabbits. Effects of stimulation frequencies and amplitudes.” Journal of the Autonomic Nervous System 1989 August; 27(3):193–205.] In general, increased frequency of electrical stimulation of the carotid sinus leads to decreased systemic blood pressure. However, the absolute frequency required for a given blood pressure may change if the carotid sinus is stimulated for an extended period of time. This study, and other more recent studies involve only acute experiments to demonstrate the potential efficacy of electrical stimulation of the carotid sinus for the treatment of hypertension. Specifically, these systems are not implantable and are not intended for chronic stimulation. In addition, these systems have no drug infusion capabilities or sensing capabilities.
What is lacking in the art, and is therefore needed, are implantable systems and methods capable of chronically providing electrical stimulation of the carotid sinus for treatment of hypertension. Ideal systems and methods also include sensing and/or drug infusion.